Axonal myelination of interneurons in cortex: functional significance and plasticity The speed and efficiency of impulse conduction in myelinated fibers is clearly fundamental to component density and functional powers of the human nervous system. There is also growing evidence that changes in myelination can have profound effects on the function of local brain circuits, including synchrony of neuronal activity and the interaction of neural oscillators. Myelin is most often thought of in association with the processes of long-axon projection neurons. But recently, we have discovered that the locally-projecting, relatively short-axon inhibitory interneurons are a major source of myelinated axons within cortical gray matter, in contrast to the myelin in white matter that forms almost exclusively on the axons of long-distance projecting excitatory neurons. In particular, interneuronal myelin appears to be confined to interneurons containing the protein parvalbumin. Synaptic inhibition is a central feature of neuronal networks. In cortex, numerous types of inhibitory interneurons participate in regulating the excitatory/inhibitory balance, in neuronal synchronization and cortical rhythms generation, and in plasticity associated with experience and learning. Even though axonal myelination defines crucial properties of neuronal transmission, it has not been specifically studied in cortical interneurons. Furthermore, pathologies of both the cortical inhibitory circuitry and of myelin are associated with many neurological and mental disorders, including multiple sclerosis, schizophrenia, and autism. Our present knowledge of myelination in the cortical gray matter, and in particular the myelination of inhibitory axons, is limited and certainly must be augmented if we are to conquer such devastating disorders. This proposal is based on a novel combination of electrophysiology and array tomography that delivers functional, structural and molecular data on individual neurons or pairs of synaptically connected neurons. The project will begin by investigating myelinated axons of parvalbumin positive basket cells and correlating their structural organization and molecular composition with the electrophysiological properties of their action potential discharge and resulting synaptic transmission onto target pyramidal neurons. Once such a baseline has been established, the contribution of axonal myelination of parvalbumin interneurons to the plasticity of neuronal circuits will be assessed using barrel cortex sensory deprivation as a model. The project will conclude with a study of the pathological changes of interneuronal myelination in a mouse model of multiple sclerosis. This proposal will provide much needed data regarding the organization of myelin of cortical interneurons, the functional consequences and the plasticity of this organization, and its potential role in multiple sclerosis.